The present invention relates to agents for the treatment of conditions of severe pain, especially tumor pain and postoperative pain, and to a process for preparing said agents.
From the EP-A-0 178 436 (Application No. 85 111 013.0) there have been known soft gelatin capsules containing ibuprofen and processes for preparing same. Said soft gelatin capsules have proven to be useful for alleviating acute pain with a rapid onset of action, since they rapidly release the active ingredient ibuprofen and, hence, create a good bioavailability of the active substance.
Cooper et al. investigated the analgetic activity of combinations of ibuprofen and codeine and determined that codeine increases the analgetic activity of ibuprofen somewhat; however, this increase was so small that it has not been considered to be of sufficient statistical significance; cf. Pharmacotherapy 1982; 2:162-167.
Abraham Sunshine et al. quote investigations on the alleviation of pain upon extraction of the rear molars (Giles and Pickvance; Frame et al.) and after episiotomy (Norman et al.). Also here it was found that the simultaneous administration of ibuprofen and codeine, although it is more effective than that of ibuprofen alone, did not reveal any statistically significant differences. According to investigations by Abraham Sunshine et al. themselves, upon episiotomy (incision for facilitating birth) only the high dose of ibuprofen plus codeine (400 mg+60 mg) exhibited an analgetic activity improved over that of ibuprofen alone. Lower doses of the combination were not better than ibuprofen (Clin. Pharm. Ther. 1987; 42: 374-380).
Thus, ibuprofen is a well tolerated and an effective analgesic which, however, is only employed against lighter and/or acute pain. For the treatment of conditions of severe pain, and especially of tumor pain and postoperative pain, it is still necessary to apply morphine or morphine derivatives. Morphine and morphine derivatives are known to cause a rapid addiction and, thus, should only be used if all remaining analgesics failed to be effective.
Therefore, it is the object of the present invention to develop an agent for the treatment of conditions of severe pain, and especially of tumor pain and post-operative pain, which does not include morphine or any morphine derivative. Surprisingly, said object can be attained by agents consisting of soft gelatin capsules containing from 30 to 50 parts by weight of ibuprofen and from 1.5 to 4 parts by weight of codeine and/or physiologically compatible salts thereof, partially dissolved and partially suspended in about 68.5 to 46 parts by weight of polyoxyethylene-polyoxypropylene-diol or in a mixture comprising about 30 to 76 parts by weight of polyoxyethylene-polyoxypropylene-diol or polyethylene-glycol or polypropyleneglycol and from about 5 to 40 parts by weight of a physiologically compatible surfactant.
A comparison to dragees containing the same amounts of ibuprofen and codeine confirmed the results reported by Cooper et al. and Sunshine et al. and has shown that such a combination is not suitable for treating severe pain conditions, and more specifically tumor pain or postoperative pain. In contrast thereto, the agent according to the invention exhibits a surprisingly good effect in many patients, comprising a very rapid onset of action on the one hand, and a relatively long duration of the action on the other hand, so that a subsequent administration must follow only relatively late. Thus, it has been found that in a great many cases the administration of morphine and/or morphine derivatives can be avoided or that such agents will be used at a substantially later stage.
Thus, the soft gelatin capsules according to the invention generally contain, in addition to the partially dissolved and partially suspended ibuprofen, the same solvents as the soft gelatin capsules of EP-A-0 178 436 (Application No. 85 111 013.0). Thus, preferably, they also contain up to 3 parts by weight of 1,2-propyleneglycol. They preferably contain polyoxyethylene-glycerol-tri-hydroxystearate, polyoxyethylene-(C.sub.12-18)-fatty alcohol ether, polyoxyethylene-stearate, polyoxyethylene-sorbitan-mono-(C.sub.12-18)-fatty acid ester, polyoxyethylene- polyoxypropylene-diol or mixtures thereof as a surfactant.
The preparation of the agents according to the invention is also carried out in a manner similar to the preparation of soft gelatin capsules containing ibuprofen, namely in a manner such that from 15 to 30 parts by weight of ibuprofen ar dissolved in 70 to 85 parts by weight of polyoxyethylene-polyoxypropylene-diol or in a mixture comprising 30 to 76 parts by weight of polyoxyethylene-polyoxypropylene-diol or polyethyleneglycol or polypropyleneglycol and 7 to 40 parts by weight of a physiologically compatible surfactant at temperatures of between 45.degree. C. and 65.degree. C., allowed to cool to room temperature, in addition up to 40 parts by weight of ibuprofen and 1.5 to 4 parts by weight of codeine and/or its physiologically compatible salts are suspended in the solution after cooling, and the mixture is incorporated in soft gelatin capsules in a per se known manner.
Particularly preferred are agents which contain from 40 to 45 parts by weight of ibuprofen and from 2.5 to 3 parts by weight of codeine phosphate . 0.5 H.sub.2 O, which in part have been dissolved and in part have been suspended in a mixture comprising .+-.rom about 86 to 90 parts by weight of polyoxyethylene-polyoxypropylene-diol, about 8 to 12 parts by weight of polyoxyethylene(40)-glycerol-tri-hydroxystearate and from about 1.5 to 2.5 parts by weight of 1,2-propyleneglycol.
They are prepared by first dissolving 20 to 25 parts by weight of ibuprofen in a warm mixture of from 86 to 90 parts by weight of polyoxyethylene-polyoxypropylene-diol, 8 to 12 parts by weight of polyoxyethylene(40)-glycerol-tri-hydroxystearate and from 1.5 to 2.5 parts by weight of 1,2-propyleneglycol, then allowing the obtained mixture to cool down to room temperature, and suspending in said mixture further 20 to 25 parts by weight of ibuprofen and 2.5 to 3 parts by weight of codeine phosphate . 0.5 H.sub.2 O, and then filling the resultant mixture into soft gelatin capsules.
These agents have been proven to be particularly valuable because they contain an especially high amount of active ingredients per weight and volume unit of the soft gelatin capsule and, nevertheless provide the active substances fast and at a high bioavailability. Thus, the capsule size or the number of capsules to be taken are within a range which is as low as possible.